WO2002035222A1 - Biocapteur - Google Patents
Biocapteur Download PDFInfo
- Publication number
- WO2002035222A1 WO2002035222A1 PCT/JP2001/009367 JP0109367W WO0235222A1 WO 2002035222 A1 WO2002035222 A1 WO 2002035222A1 JP 0109367 W JP0109367 W JP 0109367W WO 0235222 A1 WO0235222 A1 WO 0235222A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- biosensor
- reagent
- electrode
- biosensor according
- layer
- Prior art date
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- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920003226 polyurethane urea Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000013555 soy sauce Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 108010085346 steroid delta-isomerase Proteins 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- AZJYLVAUMGUUBL-UHFFFAOYSA-A u1qj22mc8e Chemical compound [F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[F-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 AZJYLVAUMGUUBL-UHFFFAOYSA-A 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
Definitions
- the present invention relates to a biosensor. Background art
- biosensors that can easily and rapidly quantify a sample containing a specific measurement target without diluting or stirring the sample have been widely used.
- a biosensor is usually provided with a working electrode (measurement method) on an electrically insulating substrate by a method such as screen printing, as disclosed in, for example, Japanese Patent No. 2517153.
- a counter electrode, and a reaction layer containing an oxidoreductase, an electron acceptor, and the like that reacts with the object to be measured is formed thereon.
- the object to be measured When the sample containing the object to be measured is brought into contact with the reaction layer, the object to be measured is oxidized by the catalytic action of the oxidoreductase, and at the same time, the electron acceptor is reduced.
- the reduced electron acceptor is reoxidized by an electrochemical method, and the concentration of the measurement target in the sample can be calculated from the oxidation current value obtained thereby.
- such a biosensor may cause a measurement error due to the physical properties of the sample.
- solid components such as blood cells contained in blood, soluble components such as lipids, proteins, and carbohydrates and insoluble components are adsorbed on the electrode surface of the biosensor. It was difficult to measure.
- the hematocrit (H et) value which is the volume ratio of red blood cells to whole blood, varies greatly depending on the sample. There was also a difference in the effects described above. The influence of such impurities can be mitigated, for example, by diluting the sample and then subjecting the sample to a biosensor, but this requires time and effort and complicates the operation.
- a method of forming a water-absorbing polymer layer on an electrode Japanese Patent Publication No. 6-53404
- a method of forming a layer containing a water-insoluble polymer and a water-soluble polymer on a reaction layer Japanese Patent Application Laid-Open No. 6-218358
- a method of forming a polymer film comprising a mixture of a fat-soluble polymer and an amphiphilic polymer on an electrode Japanese Patent Application Laid-Open No. No.
- the method using an anionic filter is effective only for solid components, and has a problem in that it has no effect on soluble components in a sample such as a protein. Further, in the other methods described above, water-soluble polymers and the like are used, so that there are problems such as high water absorption, susceptibility to humidity, and a slow enzyme reaction.
- an object of the present invention is to provide a biosensor capable of measuring an object to be measured in a sample with high accuracy without being affected by impurities or humidity in the sample.
- a biosensor of the present invention includes a substrate, a reagent layer containing a reagent, and an electrode system including a working electrode and a counter electrode, wherein the electrode system is disposed on the substrate, A bag on which the reagent layer is formed A biosensor, wherein the reagent layer further contains fine particles.
- the reagent layer formed on the electrode system contains the fine particles, impurities in the sample can be prevented from adhering to the electrode surface. Further, since there is no need to use the above-mentioned water-soluble polymer or the like, it is not affected by humidity. For this reason, regardless of the physical properties of the sample as described above, a decrease in sensitivity is prevented, and the object to be measured can be measured with high accuracy. The reason why the fine particles can prevent the adhesion of impurities to the electrode surface is unknown, but it is considered that the impurities are physically adsorbed to the fine particles.
- the reagent layer may be a single layer or a laminate including a reagent-containing layer containing the reagent and a fine-particle-containing layer containing the fine particles.
- the reagent-containing layer may be formed on the electrode via the fine-particle-containing layer.
- the fine particle-containing layer be formed on the electrode via the reagent-containing layer because the measurement target in the sample easily reacts with the reagent.
- the average particle size of the fine particles is, for example, in the range of 0.5 to 0.5 m, preferably in the range of 0.5 to 30 m, and more preferably in the range of 1 to 20 m. And particularly preferably in the range of 3 to 15.
- the average particle diameter is 0.1 m or more, the sample easily penetrates into the reagent layer easily, and the sensitivity of the biosensor can be improved.
- the average particle diameter is 45 m or less, the influence of impurities in the sample can be sufficiently eliminated.
- the average particle diameter is determined by, for example, directly observing the fine particles using an electron microscope. However, it can be obtained by measuring the particle size and calculating the average value. At this time, the measured number of the fine particles is not particularly limited, but is, for example, 100 or more, preferably 100 to 300.
- the particle size distribution of the fine particles is not particularly limited, but is preferably in the range of 0.01 to 100 m, more preferably in the range of 0.05 to 60 m, and particularly preferably.
- the average particle size is in the range of 0.1 to 40 / xm.
- the form of the fine particles may be, for example, a spherical shape, a flat spherical shape, or a shape in which the fine particles are solidified into a spherical shape.However, since the layer containing the fine particles can maintain uniform and appropriate density, it is preferable that the fine particles are spherical. Further, the fine particles are preferably formed of a polymer compound, and more preferably are a polymer compound that does not contain impurities that cause electrolysis and is electrochemically inert. Further, the polymer compound is preferably water-insoluble.
- the polymer compound include, for example, a polymer containing at least one of acrylic acid, methacrylic acid, maleic acid, acrylate, methacrylate, maleate and styrene derivative monomer. And copolymers.
- the styrene derivative polymer include styrene and alkylstyrene.
- urethane compounds such as polyurethane and polyurea
- polyolefin polymer compounds such as polyethylene and polypropylene
- polyolefin derivatives such as polyvinyl chloride
- polyamide compounds can also be used.
- polymer compound for example, it may be formed of an inorganic compound such as silica gel, alumina, zeolite, apatite, glass and ceramics represented by alite.
- acrylic acid is more preferable because it is electrochemically inert.
- PMMA polymethacrylate
- PS polystyrene
- PA polyamide
- Such fine particles include commercially available trade name Techpolymer b mx-5 (manufactured by Sekisui Plastics Co., Ltd., PMMA, spherical, particle size 5 m), trade name Gantz Pearl GM-0600 (Gantz Chemical Co., Ltd.) Gantz Pearl GS-0805 (manufactured by Ganz Kasei Co., Ltd., crosslinked PS, spherical, particle size 8 ⁇ m), trade name Gantz Pearl PS-8F (trade name) Ganz Kasei Co., Ltd., PMMA, spherical, particle size 0.4 mm), trade name Augazol 200 EXD NAT COS Type S (Elfatchem, nylon, oblong, size 10 im), trade name Trefill E_ 500 C (Toray Dow Corning Silicone Co., Ltd., cross-linked silicone powder, spherical, particle size: 10 im), trade name: Saramix Powder SN—E—02 (Ube Industries, Ltd., gay nitride
- the fine particles are electrically inactive, and it is preferable that the particle size is changed according to impurities to be removed from the sample, and the characteristics of the surface of the fine particles are changed.
- the surface properties of the fine particles are preferable, and if it is desired to be set to be more hydrophilic than PS, fine particles formed of PMMA or PA are preferable.
- fine particles formed from PS or the like into which a lipoxyl group is introduced are preferable, and when it is desired to be set to be positively charged, a PS into which an amino group is introduced is used. Formed from etc Fine particles are preferred.
- red blood cells which make up the majority of blood cell components, have an average diameter of about 7 / im.
- Erythrocyte separation can be carried out efficiently by selecting microparticles of size.
- unspecified multiplicity can be obtained by appropriately mixing PS, PS into which a lipoxyl group has been introduced, and PS having an amino group. A number of proteins can be adsorbed and removed. Note that these methods are not limited.
- the reagent layer preferably further contains an inorganic gel.
- the inorganic gel By including the inorganic gel, the adsorption of impurities to the electrode can be further prevented, and the diffusion of the sample can be prevented.Therefore, an enzymatic reaction occurs in a narrow range, so that the reagent and the analyte can react quickly. it can.
- an inorganic gel-containing layer containing an inorganic gel may be separately formed between the electrode and the reagent layer.
- a clay mineral is preferable, and examples thereof include a swellable layered silicate.
- swellable layered silicate for example, smectite and swellable mica are preferable.
- smectite for example, hectorite, savonite, montmorillonite and the like are preferable
- swellable mica for example, sodium tetrafluoride mica, teniolite and the like are preferable. Any of these may be used alone or in combination of two or more.
- smectite examples include commercially available synthetic hectorite, trade name Rabonight XLG and trade name Rabonight XLS (each manufactured by Laboratoy Industries), trade name Lucentite SWN and trade name Luo Knight SLS.
- synthetic savonites such as Sengyuit SWF (Corp Chemical Co., Ltd.) and Chikisopie W (Kyowa Chemical Co., Ltd.) Kunipia F (manufactured by Kunimine Industry Co., Ltd.) can be used.
- swellable mica examples include commercially available sodium tetrafluoride mica, trade name Na-TS (manufactured by Topi Industries), and commercially available teniolite, trade name Li-TN (manufactured by Topy Industries). And the like.
- a surfactant-containing layer containing a surfactant is formed on the reagent layer.
- a hydrophilic film is formed on the surface of the reagent layer, so that the sample and the reagent are quickly and uniformly mixed. Therefore, the reaction proceeds quickly, and the reproducibility is improved.
- a surfactant-containing layer containing a surfactant is formed on the fine particle-containing layer.
- the surfactant examples include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant, and a natural surfactant. Is a cationic surfactant, a nonionic surfactant, or a natural surfactant, and more preferably a nonionic surfactant or a natural surfactant.
- the natural surfactant include phospholipids, and preferably, lecithin such as egg yolk lecithin, soybean lecithin, hydrogenated lecithin, and high-purity lecithin can be used.
- nonionic surfactant examples include, for example, polyoxyethylene sorbitan fatty acid esters such as Tween 20 (trade name), polyoxyethylene alkyl ethers such as riro nX—'100 (trade name), and Triton nX (trade name). And polyoxyethylene phenyl alkyl ether such as —405. Of these, phospholipids are particularly preferred. Most preferably, it is lecithin such as high-purity lecithin.
- the electrode may be any electrode that can be used to electrochemically detect the reaction between the object to be measured and the sample, and examples thereof include a gold electrode, a carbon electrode, and a silver electrode.
- a gold electrode and a carbon electrode are preferred because of their excellent electrical conductivity and chemical stability, and a carbon electrode is more preferred.
- the reagent is not particularly limited as long as it reacts with an object to be measured and the reaction can be detected electrochemically.
- the reagent preferably contains an enzyme. Examples of the enzyme include oxidoreductase and the like.
- the oxidoreductase can be appropriately determined, for example, depending on the type of the measurement target. Specifically, glucose oxidase, glucose dehydrogenase, lactate oxidase, lactate dehydrogenase, fructose dehydrogenase, galactose Oxidase, cholesterol oxidase, cholesterol dehydrogenase, alcohol oxidase, alcohol dehydrogenase, pyriluvate oxidase, glucose-6-phosphate dehydrogenase, amino acid dehydrogenase, formate dehydrogenase, glycerol dehydrogenase, acyl-CoA oxidase Choline oxidase, 4-hydroxybenzoate hydroxylase, maleate dehydrogenase, sarcosine oxidase, pericase, etc. .
- the enzyme when the enzyme is an oxidoreductase, the enzyme preferably further contains an electron acceptor in the reaction of the enzyme.
- Examples of the electron acceptor include potassium ferricyanide, P-benzoquinone, phenazine methosulfate, indophenol and derivatives thereof, potassium 3- / 3-naphthoquinone-4-sulfonate, methylene blue 1. Hue mouth and its derivatives, osmium complexes, ruthenium complexes,
- NAD + , NADP +, quinoline quinoline quinone (PQQ) and the like can be used.
- the measurement sample is not particularly limited, but is useful for a sample containing impurities such as the soluble component, the insoluble component, and the solid component.
- impurities include proteins, fats, carbohydrates, and blood cells.
- Specific measurement samples include, for example, biological samples such as whole blood, plasma, serum, saliva, urine, and cerebrospinal fluid, drinking water such as juice, foods such as soy sauce, sauces, etc., drainage water, rainwater, and pool water. And the like. Among them, preferred are whole blood, plasma, serum, saliva, cerebrospinal fluid and the like, and more preferred is whole blood.
- FIG. 1 is a view showing an example of the biosensor of the present invention, (A) is a plan view thereof, and (B) and (C) are cross-sectional views thereof.
- FIG. 2 is a view showing another example of the biosensor of the present invention, (A) is a plan view thereof, and (B) and (C) are sectional views thereof.
- FIG. 3 is a cross-sectional view showing still another example of the biosensor of the present invention.
- FIG. 4 is a graph showing a correlation between a current value and an open circuit time in one embodiment of the present invention.
- FIG. 1 shows an example of the biosensor of the present invention.
- 2A is a plan view of the biosensor
- FIG. 2B is a cross-sectional view taken along the line I-I of FIG. 1A
- FIG. 1C is a sectional view of FIG.
- FIG. 2 is a cross-sectional view in the II-II direction.
- an electrode system composed of a working electrode 12 and a counter electrode 13 is arranged on a substrate 11, and on one end thereof (right side in FIG. 1 (A)).
- the two counter electrodes 13 are arranged at both ends in the width direction of the substrate 11 (in the direction of the arrow b), and the working electrode 12 is arranged at the center in the width direction of the substrate 11. 1 It extends along the long side direction (arrow a direction). Further, an insulating portion 14 is formed between the working electrode 12 and the counter electrode 13. On one end of the electrode system, spacers 15a and 15b are arranged so as to be perpendicular to the electrode system, and between the spacers 15a and 15b.
- the reagent layer 16 is arranged at the bottom.
- a cover 17 is disposed on the spacers 15a and 15b so as to cover the upper part of the reagent layer 16, and a hole penetrating in the width direction between the cover 17 and the reagent layer 16 is provided. Is formed, and this becomes the sample supply hole 18.
- the size of the biosensor 1 is not particularly limited and can be appropriately set depending on the amount of the sample to be supplied and the like.
- the overall length is 50 to 10 mm
- the overall width is 20 to 2 mm
- the maximum thickness is 1500 to 500 zm
- minimum thickness 500 to 300 m preferably total length 30 to 10 mm
- overall width 10 to 2 mm maximum thickness 1 000 to 500 m
- the size of the reagent layer 16 is, for example, 10 to 0.2 mm in length, 20 to 2 mm in width, and 400 to 5 m in thickness, preferably 5 to 0.2 mm in length and 10 to 10 in width. 2 mm, thickness 200 ⁇ : L 0 m.
- the size of the substrate 1 1 is For example, the length is 50 to 10 mm, the width is 20 to 2 mm, the thickness is 1000 to 50 m, and preferably, the length is 30 to: L 0 mm, the width is 10 to 2 mm, and the thickness is 500 to 50 m.
- the size of the spacers 15a and 15b is, for example, length 20 to lmm, width 20 to 2mm, thickness 500 to: L0 ⁇ m, preferably length 10 to 2mm and width 10 to It is 2 mm and 300 to 20 m thick.
- the size of the cover 17 is, for example, 50 to 10 mm in length, 20 to 2 mm in width, and 1000 to 50 m in thickness, preferably 30 to 10 mm in length, 10 to 2 mm in width, and 500 to 500 in thickness. 50 m.
- the size of the hole 18 is, for example, a length of 10 to 0.211, a width of 20 to 0.2 mm, a height of 500 to 5 m, preferably a length of 5 to 0.2 mm and a width of 10 to It is 2 mm high and 300 to 10 zm high.
- the “length” of each part refers to the length in the longitudinal direction of the biosensor, and the “width” refers to the length in the width direction.
- the size of the reagent layer 16 is, for example, 2 to 0.2 mm in length, 20 to 2 mm in width, and 400 to 5 m in thickness, and preferably It has a thickness of 1 to 0.4 mm, a width of 10 to 2 mm, and a thickness of 200 to 10 m.
- the size of the hole 18 is, for example, 2 to 0.2 mm in length, 20 to 2 mm in width, and 500 to 50 m in height, and is preferably a length; ⁇ 0.4mm, width 10 ⁇ 2mm, height 300 ⁇ : 100m.
- the content of the fine particles in the reagent layer 16 can be appropriately determined depending on the type of the sample to be supplied, the amount thereof, and the like, and is, for example, in the range of 1 to 0.01 mg for about 2 L of the sample, Preferably, it is in the range of 0.5 to 0.05 mg.
- the content of the reagent in the reagent layer 16 is not particularly limited, and can be appropriately determined according to the type of the reagent, the type and the amount of the sample, and the like.
- an enzyme when used as a reagent, its content is preferably 50 to 0.05 U, more preferably 20 to 0.1 U, for about 2 L of the sample.
- an electron acceptor when used, its content is preferably 100 to 0.01 mol, more preferably 50 to 0.05 mol, per 2 L of the sample.
- G ⁇ D is used as the enzyme and potassium ferricyanide is used as the electron acceptor
- GOD 20-0.1 U and potassium ferricyanide 50-0.05 ⁇ 1 are used for about 2 L of the sample. More preferably, the GOD is 10 to 0.2 U, and the potassium phenylate is 10 to 0.1 mol.
- Such a biosensor can be manufactured, for example, as described below.
- a substrate 11 for forming the electrodes and the like is prepared.
- the material of the substrate 11 is preferably electrically insulating, and examples thereof include plastic, glass, paper, and ceramics.
- the plastic include polyethylene terephthalate (PET), PS, PMMA, polypropylene (PP) and the like.
- an electrode system including a working electrode 12 and a counter electrode 13 is formed on the substrate 11.
- the electrode is preferably a gold electrode, a carbon electrode, or the like, and can be formed by a known method according to the type.
- the gold electrode can be formed by, for example, an evaporation method, a plating method, a gold foil sticking method, or the like.
- the deposition process can be carried out, for example, by vacuum 1. 3 3 X 1 0- 4 P a, the input path Wa 300 W, rate 5 A / sec, ion plating ting method under the conditions of time 2 minutes.
- This is, for example, a method in which gold is deposited on a plastic sheet such as PET, and a kiss cut device is used to make a cut in the gold foil layer deposited on the shield. Thereby, the cut portion becomes an insulating portion, and a working electrode and a counter electrode can be formed.
- a carbon ink can be formed on the substrate 11 by means of screen printing, coating, plating, or the like.
- a hydrophilization treatment it is preferable that the electrode surface is subjected to a hydrophilization treatment. Thereby, even if the electrode surface is hydrophobic, the electrode surface is hydrophilized by the treatment, so that when the reagent layer is formed using the reagent solution as described later, the reagent layer is easily formed uniformly.
- the hydrophilic treatment can be appropriately determined depending on the type of the electrode.
- the electrode is a gold electrode, for example, the electrode may be immersed in a hydrophilizing solution such as a mercaptoethanol solution or a mercaptoethanol solution, and then washed and dried.
- the solvent for the hydrophilic solution examples include organic solvents such as ethanol, butanol, acetone, and tetrahydrofuran.
- the concentration of the hydrophilizing solution is, for example, in the range of 100 to 0.01 mmO1ZL, and preferably in the range of 50 to 0.05 mmO1ZL.
- an organic solvent such as ethanol, methanol, butanol, acetone, and tetrahydrofuran
- a washing solution such as purified water
- the electrode is a carbon electrode, for example, the electrode can be hydrophilized by a method of immersion in a surfactant and washing with purified water.
- spacers 15a and 15b are arranged on the substrate 11 on which the electrode system is formed. As shown, by arranging the two spacers 15a and 15b in parallel with each other at a fixed interval in the width direction, a formation portion of a reagent layer 16 described later can be secured.
- a resin film or tape can be used as the material of the spacer 15, for example.
- a cover described later can be easily bonded.
- a spacer can be formed by, for example, means such as resist printing.
- a single-layer reagent layer 16 containing a reagent and fine particles is formed in the gap between the spacers 15a and 15b.
- This reagent layer can be formed by preparing a solution containing the fine particles and various reagents and injecting the solution into the gap of the spacer 15.
- the solution is preferably prepared by, for example, dissolving a reagent sufficiently and further dispersing the fine particles.
- the solvent is not particularly limited, but for example, water, a buffer, an organic solvent such as ethanol, methanol, butanol, dimethyl sulfoxide (DMSO), and tetrahydrofuran can be used.
- the buffer examples include a phosphate buffer, a citrate buffer, an acetate buffer, a Tris-HCl buffer, a Good buffer, and the like, and the pH thereof is preferably in the range of 4 to 9, and more preferably. It is in the range of 5-8.
- the water examples include purified water, distilled water, and ultrapure water. Among them, ultrapure water is preferable because it has a very small amount of impurities and can produce a high-precision biosensor.
- the concentration of the fine particles in the solution is not particularly limited, but is preferably in the range of 1,000 to 10 g / L, and more preferably in the range of 500 to 50 g / L. '
- the concentration of the reagent in the solution is not particularly limited.
- it is preferably in the range of 10,000 to 10 KUZL, and more preferably in the range of 5,000 to 50 KUZL.
- the range is preferably 10 to 0.01mo1 ZL, and more preferably the range is 5 to 0.05mb1 ZL.
- the solution is injected into the gap between the spacers 15a and 15b.
- the injection is not particularly limited, and can be performed using, for example, an automatically driven dispenser.
- Injection amount of the solution, the size of the formed reagent layer, can be appropriately determined by the content and the like of the fine particles and reagents, area 1 0 mm 2 per 10 forming
- the range is preferably from 0.1 to 0.1 L, more preferably from 5 to 0.2 L.
- a reagent layer After the injection, this is dried to form a reagent layer.
- the means for drying is not particularly limited, and for example, methods such as natural drying, air drying, vacuum drying, and freeze vacuum drying can be employed. Further, these means may be combined.
- the conditions are, for example, a temperature range of 10 to 60 ° C, a relative humidity RH of 5 to 40%, and a time period of 1 to 30 minutes.
- a cover 17 is arranged on the spacers 15a and 15b so as to cover the reagent layer 16.
- the pores formed between the reagent layer 16 and the cover 17 become the sample supply holes 18.
- the material of the cover 17 is not particularly limited, and for example, various plastics can be used.
- the biosensor 1 When the biosensor 1 thus manufactured is stored for a long period of time, it is preferable that the biosensor 1 be sealed and stored together with a desiccant such as molecular sheep, silica gel, or calcium oxide in order to prevent the influence of moisture.
- a desiccant such as molecular sheep, silica gel, or calcium oxide in order to prevent the influence of moisture.
- the biosensor 1 includes, for example, a unit that applies a predetermined voltage for a certain period of time, a unit that measures an electric signal transmitted from the biosensor, and a calculation unit that calculates the concentration of the electric signal to be measured. It can be used in combination with measuring instruments equipped with various means.
- the method of using the biosensor 1 will be described using an example in which the sample is whole blood, the measurement target is glucose, and the reagents are GOD and ferricyanide force rim.
- a whole blood sample is sucked into the hole 18 of the biosensor 1 by capillary action or the like. Then, the presence of the fine particles prevents impurities in whole blood such as blood cells from adhering to the electrode.
- glucose in whole blood is oxidized by the GOD of the reagent layer 16 and is transferred by electrons transferred by the oxidation reaction. Then, the ferricyanide power is reduced to produce a ferrosyanide power dream.
- a voltage is applied between the counter electrode 13 and the working electrode 12 by the voltage applying means, and the reduced ferrocyanation force rim is electrochemically applied.
- the oxidation current at that time is detected by means for measuring the electric signal. Since the peak value of the oxidation current is proportional to the glucose concentration in the sample, the glucose concentration in the sample can be obtained by calculating this value into the glucose concentration by the calculating means. According to such a biosensor, the impurity in the sample does not adsorb to the electrode as described above, so that a decrease in sensitivity is prevented and measurement can be performed with high accuracy. It is not affected by humidity.
- the reagent layer may further contain an inorganic gel.
- the inorganic gel those described above can be used.
- the content of the inorganic gel in the reagent layer can be appropriately determined depending on the type of the inorganic gel, the type of the sample, the amount thereof, and the like. For example, 100 to 0.1 g for about 2 L of the sample And preferably in the range of 50 to 0.5 g.
- the reagent layer containing such an inorganic gel may be formed in the same manner as described above by preparing a solution containing the above-mentioned reagent, microparticles and inorganic gel.
- FIG. 2 shows another example of the biosensor of the present invention.
- FIG. 3A is a plan view of the biosensor
- FIG. 3B is a cross-sectional view taken along the line III-III of FIG. 3A
- FIG. 3C is a cross-sectional view of FIG. IV—a sectional view in the IV direction.
- the same parts as those in FIG. 1 are denoted by the same reference numerals.
- this biosensor 2 has a working electrode 12 and a working electrode 12 on a substrate 11.
- An electrode system composed of an electrode system 13 and a counter electrode 13 is arranged.
- an inorganic gel-containing layer 21, a reagent layer 16 and a surfactant are provided at one end (upper right in FIGS. 7A and 7B).
- a laminate is formed by laminating the containing layer 22 in this order.
- the reagent layer 16 contains a reagent and fine particles.
- the two counter electrodes 13 are arranged at both ends in the width direction (arrow b direction) of the substrate 11, and the working electrode 12 is arranged at the center in the width direction of the substrate 11, and these electrodes 12, 13 are arranged on the substrate 11. 11.
- a first spacer 15a, 15b is arranged to be perpendicular to the electrode system, and between the spacers 15a, 15b.
- the stacked bodies 21, 16, and 22 are arranged at the center.
- second spacers 23a and 23b there are further disposed second spacers 23a and 23b.
- a cover 24 is arranged on the second spacers 23 a, 23 b so as to cover the upper portions of the laminates 21, 16, 22, and the cover 24 and the laminate 21, A hole extending in the width direction is formed between 16 and 22, and this becomes a sample supply hole 18.
- the biosensor 2 has the same configuration as the biosensor of the first embodiment, unless otherwise specified.
- the content of the inorganic gel in the inorganic gel-containing layer 21 can be appropriately determined according to the type and amount of the sample to be supplied, the type of the inorganic gel, and the like. It is in the range of 0.1 g, and preferably in the range of 500 to 0.5 g.
- the content of the surfactant in the surfactant-containing layer 22 can be appropriately determined according to the type and amount of the sample to be supplied, the type of the surfactant, and the like. It is in the range of 0-0.05 Og, preferably in the range of 50-0.05 g.
- the inorganic gel containing layer 21, the reagent layer 16 and the surfactant containing The biosensor 2 in which the layers 22 are stacked can be manufactured, for example, as described below. In addition, unless otherwise indicated, it is manufactured in the same manner as in the first embodiment.
- a solution containing an inorganic gel is prepared, and the spacers 15a and 15a are prepared. Inject into the gap of 5b and dry. Subsequently, in the same manner, the solution containing the reagent and the fine particles and the solution containing the surfactant are respectively poured and dried, and the inorganic gel-containing layer 21, the reagent layer 16 and the surfactant-containing layer 22 are sequentially formed. Laminate.
- a second spacer 23 a, 23 b is laminated on the first spacer 15 a, 15 b, and the second spacer 23 a, 2 A cover 24 is disposed on 3 b so as to cover the upper surface of the surfactant-containing layer 22.
- the pores formed between the surfactant-containing layer 22 and the cover 24 become the sample supply holes 18.
- the second spacer when the second spacer is formed, the height of the hole 18 can be adjusted.
- the second spacer can be made of the same material as the first spacer, and can be formed in the same manner.
- the solution containing the inorganic gel is preferably stirred for 1 hour or more, more preferably for 5 hours or more, in order to prevent the inorganic gel from settling. Further, for the same reason, it is preferable to continue stirring during use.
- the concentration of the inorganic gel in the solution is not particularly limited, but is, for example, in the range of 10 to 0.001% by weight, and preferably in the range of 5 to 0.05% by weight.
- This embodiment is an example of the biosensor of the present invention in which the reagent layer is a laminate of the reagent-containing layer and the fine particle-containing layer.
- This biosensor is shown in the cross-sectional view of FIG. In the figure, the same parts as those in FIG. I have.
- the biosensor 3 has the same configuration as that of the first embodiment except that a fine particle-containing layer 32 is laminated on a substrate 11 on which electrodes are arranged via a reagent-containing layer 31. It is.
- the reagent-containing layer 31 and the fine particle-containing layer 32 are prepared, for example, by preparing a solution containing a reagent and a solution containing fine particles, injecting the solution containing the reagent into the gap between the spacers, and drying the solution. It can be formed by injecting a solution containing the fine particles and drying the solution.
- an inorganic gel-containing layer is separately formed on the electrode,
- the reagent-containing layer or the like may be formed on the inorganic gel layer, or a surfactant-containing layer may be further laminated on the fine particle-containing layer.
- biosensor of the present invention is not limited to the above embodiments.
- all layers may contain fine particles, inorganic gel, or both.
- a gold electrode biosensor similar to that of FIG. 2 was produced.
- a transparent PET sheet (hereinafter, the same) having a length of 30 cm, a width of 30 cm, and a thickness of 250 m was prepared as a support, and one surface thereof was subjected to gold vapor deposition.
- the deposition conditions are the same as described above.
- the purity of the gold used is greater than 99.95%.
- a depth of 0.1 mm was applied to the gold deposition surface of the PET sheet.
- mm 0.1 mm wide straight line cuts were made alternately at 1 mm and 5 mm intervals in one direction (hereinafter referred to as “Haf cut”).
- This cut portion becomes an insulating portion 14, and the deposited gold is divided into a working electrode 12 and a counter electrode 13.
- the width of the working electrode 12 of the biosensor is 1 mm
- the width of the counter electrode 13 is 2.5 mm
- the width of the insulating part 14 is 0.1 mm.
- the PET sheet was cut to have a length of 20 mm and a width of 170 mm using a cutting device (trade name: MatriX 2360, manufactured by KINEMATIC).
- the cut sheet was immersed in 1 Ommo 1 ZL 2 -mercaptoethanol solution (solvent: ethanol) for 30 minutes, washed with ethanol and then with purified water, and dried at room temperature in a clean bench.
- the gold-deposited surface was hydrophilized.
- two single-sided tapes made of polyamide manufactured by Sumitomo 3LEM Co., Ltd., product name: Y-55579, thickness: 42 m
- the first spacers 15a and 15b were applied to the gold vapor deposition. It was affixed to a predetermined position on the surface. In this case, the distance between the spacer 15a and the spacer 15b is 1 mm, the length of the spacers 15a and 15b is 5 mm, and the width is 17 Omm. I did it.
- an inorganic gel-containing layer 21 was formed in a gap between the spacers 15a and 15b.
- 150 mg of inorganic gel (Cup Chemical Co., Ltd., trade name: Lucentite SWN) and 50.0 g of purified water were placed in a silicone-treated wide robin, and stirred overnight at room temperature (500 rms for 10 hours or more). )
- liquid A a raw material liquid for the inorganic gel-containing layer 21
- the solution A was dispensed using a syringe into the gap between the first spacers 15a and 15b of the PET sheet.
- the dispensing amount of the solution A is the dispensing surface 1.74 L for an area of 6 mm X lmm (equivalent to one biosensor). After the dispensing, this was allowed to dry at room temperature for 30 minutes or more in a clean bench or desiccator.
- the inorganic gel-containing layer 21 was formed by drying in an atmosphere at 35 ° C. and a relative humidity of 10% or less for 30 minutes using a drier (hereinafter, referred to as “honey dry drying”).
- a single-layer reagent layer 16 containing fine particles, an inorganic gel and a reagent was formed on the inorganic gel-containing layer 21.
- a raw material liquid for the reagent layer 16 (hereinafter, referred to as “solution B”) was prepared. 400 mg of the inorganic gel (the above-mentioned Lucentite SWN) and 50.0 g of purified water were put into a silicone-treated wide-mouth bottle, and stirred at room temperature (at least 10 hours, 500 rpm). Into a brown bottle, add 1.0 mL of the inorganic gel solution, 3.
- the solution B was dispensed on the surface of the inorganic gel-containing layer 21 on the sheet using a dispensing device (trade name: Dispenser System, manufactured by Bio Dot).
- the dispensing amount of the solution B was 1.30 ⁇ L with respect to the dispensing surface area of 6 mm x lmm (corresponding to one biosensor). After dispensing, this was dried in an oven at 50 ° C. in a windless state for 10 minutes, and the above-mentioned honey dry drying was similarly performed for 10 minutes to form a reagent layer 16. Next, a surfactant-containing layer 22 was formed on the reagent layer 16.
- C solution the raw material solution of the surfactant-containing layer 22 (hereinafter, referred to as "C solution") was prepared.
- the solution C was dispensed on the surface of the reagent layer 16 of the sheet 11 using the dispensing device.
- the dispensed amount of the solution C was 0.3 OL with respect to the dispensed surface area of 6 mm x i mm (corresponding to one biosensor).
- a double-sided PET film core double-sided tape (Dai Nippon Ink Co., Ltd., trade name: Dedac double-sided adhesive tape, thickness: 150 im) was used. , Placed on 15b.
- One second spacer 23 a has a length of 5 mm and a width of 160 mm
- the other second spacer 23 b has a length of 5 mm and a width of 160 mm.
- a PET film having a length of 15 mm, a width of 160 mm, and a thickness of 188 m is attached so as to cover the second spacers 23a and 23b and the gap therebetween.
- hippo 24 a double-sided PET film core double-sided tape
- the obtained laminate was cut by the cutting device to a width of 6 mm to produce a target biosensor having a length of 20 mm and a width of 6 mm.
- the biosensor was stored in brown bottles with 3 g or more molecular sieves until use. (Example 2)
- the Lucenite SW A biosensor was produced in the same manner as in Example 1 except that Rabotite XL S (manufactured by Laborte) was used instead of N.
- a biosensor was prepared in the same manner as in Example 1 except that in the preparation of the solution B, 1. OmL of purified water was used instead of 1. OmL of the inorganic gel solution.
- the working electrode 12 and the counter electrode 13 were formed by applying carbon printing to one surface of the transparent PET sheet to be the substrate 11 by using a pressure ink. Printing was performed using a screen printing machine, under the following conditions: SUS300 mesh, squeegee pressure 3 to 5 MPa, print speed 0.5 mZs, coat speed 0.5 m / s, clearance 2. Omm The contact was 15 degrees. The sheet was dried at 90 ° C. for 30 minutes.
- resist printing is performed on the electrode side surface of the PET sheet using a resist ink containing an insulating UV curable resin as a main component, and this is dried to form a first spacer 15a, 15b.
- This resist printing is Using a clean printing machine, the conditions are polyester 250 mesh, squeegee pressure 3-5 MPa, print speed 0.15 mZs, coat speed 0.15 m / s, clearance 4.Omm, off-contact 15 degrees And
- the size and the like of the first spacer were set in the same manner as in Example 1, and the thickness of the first spacer was adjusted so that the thickness after drying described later becomes 10. The drying was performed using a UV dryer under the condition of 3.7 mZs.
- an inorganic gel-containing layer 21 was formed in the gap between the spacers 15a and 15b.
- the Rabonit XL S15 Omg was used instead of the lucentite S WM as an inorganic gel, and the dispensed amount of the solution A was a dispensed surface area of 6 mm x lmm (equivalent to one sensor). Was set to 1.45 L.
- Solution B as a raw material was prepared as follows. 3. OmL of purified water, 75 Omg of the fine particles described above and 24 Omg of potassium ferricyanide were placed in a brown bottle and stirred, and a potassium ferricyanide solution was prepared by completely dissolving the potassium ferricyanide. Subsequently, in another brown bottle, 2.40 KU of glucose oxidase and 2.OmL of the lysium ferricyanide solution were added, and the mixture was sufficiently stirred until the mixture became homogeneous. The dispensing amount of the solution B was 1.08 L with respect to the dispensing surface area of 6 mm X lmm (corresponding to one sensor).
- Example 6 Thereafter, in the same manner as in Example 1, a laminate was prepared by forming the surfactant-containing layer 22 and arranging the second spacers 23a, 23b and the cover 24. This was cut to obtain the target biosensor. (Example 6)
- a biosensor was produced in the same manner as in Example 5, except that the inorganic gel-containing layer 21 was not formed. (Comparative Example 1)
- a conventional biosensor was manufactured as follows. First, a carbon electrode was formed on the PET sheet in the same manner as in Example 5, and a spacer was formed in the same manner as in Example 1. Then, after preparing a 3% by weight aqueous solution of carboxymethylcellulose (CMC), this was dispensed on the electrode system of the PET sheet and dried to form a CMC layer. The dispensed amount of the CMC solution was 3 L for a dispensed surface area of 6 mm ⁇ 1 mm. Next, add 3.2 mg of potassium ferricyanide to 4.0 mL of purified water, stir the mixture completely, and add 2.40 KU of glucose oxidase to 2 mL of this aqueous potassium ferricyanide solution. Stirred.
- CMC carboxymethylcellulose
- This reagent solution was dispensed on the CMC layer and dried in the same manner as in Example 1 to form a reagent layer.
- the dispensed amount of the reagent solution was 1.30 ⁇ L for the dispensed surface area of 6 mm x 1 mm.
- the second spacer was arranged, and a cover was attached.
- Various tests described below were performed on the biosensors of each of the examples and comparative example 1 obtained as described above.
- the current value was measured for each of the biosensors of Examples 1 to 4 and the biosensor of Comparative Example.
- physiological saline hereinafter referred to as “Sa1”
- GSa1 physiological saline
- WB human Blood
- P human plasma
- WB human whole blood
- P human plasma
- the Het of the human whole blood (WB) was 46%
- the glucose concentration in the plasma of human whole blood (WB) and human plasma (P) was 127 OmgZL.
- each biosensor was connected to a potentiometer (BAS, product name: CV100W), the sample was aspirated into the biosensor at room temperature, and the open circuit state was maintained for 25 seconds. Then, the current value at the time when the voltage was applied for 5 seconds was measured. The voltage was set to 25 OmV for the sensors of Examples 1-4 and 50 OmV for the biosensor of the comparative example. The current value was measured three times for each biosensor and each sample under the same conditions, and the average value was obtained. For each biosensor, the divergence rate A () and divergence rate B (%) were determined by the following equations (1) and (2), respectively.
- E S al, E GS al , The E WB and E P wherein an average value of said current value when measured with each sample.
- the divergence rate A and the divergence rate B are values indicating the degree of the influence of impurities in the sample, and the divergence rate A is a value mainly related to the influence of blood cells, and the divergence rate B is It is a value related to the influence. It can be determined that the smaller these absolute values are, the smaller the influence of the impurities is.
- Deviation rate A (%) [(E WB -E P ) / E P ] XI 00
- Deviation rate B (%) [(E WB -E P ) / (E P -E S a !)] XI 00
- Table 1 shows the average value of the current values, and the divergence rates A and B calculated from the equations (1) and (2) using the average values.
- the current value was measured using the gold electrode biosensor of Example 4 in order to investigate the effect of the open circuit time.
- physiological saline containing glucose concentration: 500 Omg / L was used.
- FIG. 3 is a graph showing a correlation between an open circuit time and a current value. As shown in Fig. 4, the current value was hardly affected by the open circuit time. This indicates that, in the biosensor of Example 4, the enzyme reaction rapidly progressed in a short time after aspirating the sample. From this, it can be said that the biosensor of the present invention is capable of quick measurement and has excellent operability. (Confirmation of the effect of Hct on the carbon electrode sensor)
- the current values of the carbon electrode biosensor of Example 5 and the gold electrode biosensor of Example 4 and the biosensor of Comparative Example were measured.
- Physiological saline (Sal), human whole blood (WB), and human plasma (P) were used for the biosensors of Examples 4 and 5, respectively.
- Human whole blood (WB) and human plasma (P) were used.
- the Het of the human whole blood (WB) was 49%, and the plasma glucose concentration of human whole blood (WB) and human plasma (P) was determined to be 110 mg / L.
- the gold electrode biosensor of Example 4 and the carbon electrode biosensor of Example 5 were respectively connected to the potentiostat. Then, after aspirating the sample into the biosensor, a current value was measured when a voltage was applied for 20 seconds. The voltage was 250 mV for the gold electrode sensor and 35 OmV for the carbon electrode sensor.
- the biosensor of the comparative example after the sample was connected to the potentiostat and the sample was sucked into the biosensor, the circuit state was held for 25 seconds, and the current value at the time when the voltage was applied for 5 seconds was measured. Was measured. About each biosensor Under the same conditions, the current value was measured four times, and the average value was obtained. The divergence rate A (%) and the divergence rate B (%) were determined in the same manner as described above. Table 2 below shows the average value of the current values and the results of the deviation rate A and the deviation rate B.
- Deviation rate A (%) ⁇ 1.0 -6.0 ⁇ 8.2
- the absolute value of the deviation rate A in the biosensor of both examples is smaller than the absolute value of the deviation rate A in the biosensor of the comparative example.
- the absolute value of the deviation rate B in both examples was almost the same as the absolute value of the deviation rate A, respectively.
- the gold electrode biosensor of Example 4 The force of Example 5 and Example 6, and the biosensor of Comparative Example
- the current value was measured by the following method in order to investigate the influence of the current.
- the current value was measured using an unused biosensor that was sufficiently dried.
- Physiological saline (S a1) and physiological saline (GS a1) supplemented with glucose (concentration 10 Omg / L) were used as samples.
- a biosensor was connected to the potentiostat, and after the sample was aspirated into the biosensor, the open circuit state was maintained for 25 seconds. Then, the current value at the time when the voltage was applied for 5 seconds was measured.
- the voltage was set at 25 OmV for the gold electrode biosensor of Example 4, 35 OmV for the carbon electrode biosensors of Examples 5 and 6, and 500 mV for the biosensor of Comparative Example. did.
- the current value was measured twice under the same conditions, and the average value was determined.
- the biosensor of the present invention is not easily affected by substances other than the object to be measured, such as solid components, soluble components, and insoluble components in the sample, and by humidity. It is possible to measure. In addition, operability is excellent because the enzyme reaction proceeds quickly.
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Abstract
Priority Applications (5)
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AU2002210940A AU2002210940A1 (en) | 2000-10-27 | 2001-10-25 | Biosensor |
US10/399,874 US6982027B2 (en) | 2000-10-27 | 2001-10-25 | Biosensor |
JP2002538156A JP3713522B2 (ja) | 2000-10-27 | 2001-10-25 | バイオセンサ |
EP01978899A EP1336839B1 (fr) | 2000-10-27 | 2001-10-25 | Biocapteur |
AT01978899T ATE543092T1 (de) | 2000-10-27 | 2001-10-25 | Biosensor |
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EP (1) | EP1336839B1 (fr) |
JP (1) | JP3713522B2 (fr) |
CN (1) | CN100335894C (fr) |
AT (1) | ATE543092T1 (fr) |
AU (1) | AU2002210940A1 (fr) |
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JP2005526260A (ja) * | 2002-05-17 | 2005-09-02 | オックスフォード バイオセンサーズ リミテッド | 分析対象物計測 |
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JP4800209B2 (ja) * | 2003-06-20 | 2011-10-26 | エフ ホフマン−ラ ロッシュ アクチェン ゲゼルシャフト | テストストリップ用の試薬ストライプ |
JP2007524824A (ja) * | 2003-06-20 | 2007-08-30 | エフ ホフマン−ラ ロッシュ アクチェン ゲゼルシャフト | テストストリップ用の試薬ストライプ |
JP2011203268A (ja) * | 2003-06-20 | 2011-10-13 | F Hoffmann-La Roche Ag | テストストリップ用の試薬ストライプ |
WO2005043146A1 (fr) * | 2003-10-30 | 2005-05-12 | Arkray, Inc. | Biocapteur et procede de fabrication associe |
CN100456032C (zh) * | 2003-10-30 | 2009-01-28 | 爱科来株式会社 | 生物传感器及其制造方法 |
JP4566064B2 (ja) * | 2005-05-16 | 2010-10-20 | 独立行政法人産業技術総合研究所 | 竹型カーボンナノチューブを用いたバイオセンサ |
JP2006317360A (ja) * | 2005-05-16 | 2006-11-24 | National Institute Of Advanced Industrial & Technology | 竹型カーボンナノチューブを用いたバイオセンサ |
WO2009057792A1 (fr) * | 2007-10-31 | 2009-05-07 | Arkray, Inc. | Instrument d'analyse |
JP5081249B2 (ja) * | 2007-10-31 | 2012-11-28 | アークレイ株式会社 | 分析用具 |
US8384402B2 (en) | 2007-10-31 | 2013-02-26 | Arkray, Inc. | Analysis tool |
JP2011506969A (ja) * | 2007-12-10 | 2011-03-03 | バイエル・ヘルスケア・エルエルシー | バイオセンサーのための多孔性粒子試薬組成物、装置及び方法 |
JP2009244012A (ja) * | 2008-03-31 | 2009-10-22 | Cci Corp | バイオセンサ |
JP2018036091A (ja) * | 2016-08-30 | 2018-03-08 | アークレイ株式会社 | バイオセンサ、及びその製造方法 |
US10619178B2 (en) | 2016-08-30 | 2020-04-14 | Arkray, Inc. | Biosensor and production method for same |
Also Published As
Publication number | Publication date |
---|---|
CN100335894C (zh) | 2007-09-05 |
EP1336839A4 (fr) | 2006-05-24 |
ATE543092T1 (de) | 2012-02-15 |
JP3713522B2 (ja) | 2005-11-09 |
EP1336839A1 (fr) | 2003-08-20 |
JPWO2002035222A1 (ja) | 2004-03-04 |
EP1336839B1 (fr) | 2012-01-25 |
US20040040839A1 (en) | 2004-03-04 |
AU2002210940A1 (en) | 2002-05-06 |
CN1471638A (zh) | 2004-01-28 |
US6982027B2 (en) | 2006-01-03 |
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